Synthesis of 1,4-dicaffeyl-quinic acid



Un t d States Patent SYNTHESIS OF 1,4-DICAFFEYL-QUINIC ACID AlbertoVercellone, Milan, and Luigi Panizzi, Rome,

Italy, assignors to Societa Farmaceutici Italia, Milan,

Italy, a corporation of Italy No Drawing. Filed Dec. 27, 1955, Ser. No.555,283

Claims priority, application Italy Dec. 28, 1954 6 Claims. (Cl. 260-473)n"-o-Oon=on-o on wherein R represents chlorine and 0o0011=o11 0-R' andR, R" individually represent carbomethoxy, carboethoxy and'carbobenzoxy,and jointly represent carbonyl, with a compound of the group consistingof quinide and the 4,5-alkylidene derivatives of quinide correspondingto the formula wherein X, Y individually represent hydrogen and jointlyrepresentv alkylidene (isopropylidene), to obtain intermediates of thegeneral formula wherein X, Y, Z individually represent the radical Zrepresents said radical while X and Y jointly represent allcylidene(isopropylidene) and X, Z individually represent said radical while Yrepresents hydrogen, and subjecting these intermediates to a selectivesaponification to obtain compounds of the general formula COOH in whichthe carboxyl can be esterified with the hydroxyl in -y-position to formthe quinide lactone ring and wherein at least one of T, V, W representshydrogen and at least one other represents We have now found that, inorder to synthesize 1,4di-

Patented Sept. 12, 1961 cafi'eyl-quinic acid, instead of a cafleic acidderivative of Formula I, the chloride of thionyl-caffeic acid may beused and, in lieu of quinide (lactone of quinic acid), quinic acid i oncoon

itself. The 1,4-dicafieyl-quinic acid is then obtained by selectivelysaponifying the reaction product in treating it with a 3% bariumhydroxide solution, followed by acid ification.

Obviously, the same result is obtained upon condensing the chloride ofthionyl-catfeic acid with quinide, or upon condensing chlorides ofcarboalkyloxy or carboaryloxy acids of a cafieic acid derivative definedby the general Formula I with quinic acid, as described in theafore-mentioned co-pending patent application. However a specialadvantage of the present invention is that use of the quinide is notnecessary. Since the quinide is generally derived from quinic acid, thedirect reaction of the latter provides a more economical process.

Condensation is accomplished by mixing 1 to 4 mols of an acyl derivativeaccording to the general Formula I with 4 to 1 mols of quinic acid orquinide and heating the mixture for fifteen to ninety minutes to atemperature from. to 180 C. and then selectively saponifying by treatingthe condensation product with 3% barium hydroxide solution at 0 to 30 C.for a period of one to forty hours while excluding the access of air.The chloride of thionyl-caffeic acid is obtaned by refluxing caffeicacid with an excess of thionylchloride until dissolution occurs, andevaporation of thionyl chloride until crystallization takes place. Thechloride of thionylcaffeic acid can then be recrystallized from an inertsolvent (hydrocarbon, chlorinated hydrocarbon).

The following examples are presented to illustrate the invention but inno way to restrict the scope thereof.

Example 1 10.0 g. of carbonyl-cafieic acid chloride are mixed with 2.86g. of quinic acid and heated slowly under vacuum to a temperature of 160C. which is then maintained for twenty to thirty minutes. After cooling,the molten mass is taken up with acetone and poured into 1 liter of 3%barium hydroxide solution While working in a nitrogen atmosphere toavoid access of air. After forty hours, the yellow precipitate isfiltered off and suspended in cc. of 2 N HCl. The suspension isfiltered, the cake treated with a 10% sodium bicarbonate solution,filtered, Washed with 2 N HCl and water, and finally dissolved in hot55% acetic acid. 1,4-dicafleylquinic acid crystallizes, having a M.P. of225-227 C., (a) =66i1 (c.=2.0: ethanol).

Example 2 10.0 g. of thionyl-cafieic acid chloride are condensed with3.56 g. of quinide in the manner indicated in Example 1. A molten massis obtained, which is dissolved in dioxane and poured into 1 liter of 3%barium hydroxide solution, while operating in a nitrogen atmosphere.Proceeding according to Example 1, 1,4-dicaffeyl-quinic acid, having a-M.P. of 224-227 C. (decomposition), is obtained.

The chloride of thionyLcatfeic acid is prepared by boiling 30 g. ofcatfeic acid with 90 cc. of thionyl chloride;

after seven to eight hours a brown solution is obtained,

which is evaporated to dryness under vacuum. By re- 10.0 g. ofthionyl-cafieic acid chloride and 3.93 g. of quinic acid are heatedunder vacuum within a period of 1.5 hours to 155 C. A molten mass isobtained, which is dissolved in dioxane and poured into 1000 cc. of 3%barium hydroxide solution, while operating under an inert gas. Afterforty hours standing, the yellow precipitate is filtered ofi? andtreated first with dilute HCl, then with sodium bicarbonate and againwith more diluted HCl. The crude 1,4-dicaffeyl-quinic acid thus obtainedis purified in the usual manner from aqueous acetic acid.

I We claim:

1. The process of synthesizing 1,4-dicafieyl-quinic acid,

. m-oOonmsm-oo 01 wherein R, R? individually represent members of thegroup consisting of carbomethoxy, carboethoxy and car- 4. The process ofsynthesizing 1,4-dicatfeyl-quinic acid,

" which comprises condensing 1 to 4 mols of the chloride ofthionyl-cafleic acid with 4 to 1 mols of quinic acid by heating forfifteen to ninety minutes to 110-180 C. and saponifying the condensationproduct with a 3% barium hydroxide solution for one to forty hours at 0to 30 C. in the absence of air. I T I i v 5. The process of synthesizing1,4-dicafieyl-quinic1 acid, which comprises condensing 1 to 4 mols ofcafl'eic acid derivative of the type 1 a wherein R, 'R" individuallyrepresent members of the group consisting of carbomethoxy, carboethoxyand carbobenzoxy, and jointly represent members of the group consistingof carbonyl and thionyl, with 4 to 1 mols of quinic acid by heating forfifteen to ninety minutes at about 110180 C. and saponifying thecondensation product with aqueous barium hydroxide.

6. The process of synthesizing 1,4-dicafieyl-quinic acid,

7 comprising boiling caflfeic acid with thionyl chloride to bobenzoxy,and jointly represent members of the group consisting of carbonyl andthionyl, with quinic acid and saponifying the condensation product witha 3% barium hydroxide solution at 0 to C. in the absence of air.

2. The process according to claim 1, wherein the chloride ofthionyl-caffeic acid is condensed with quinic acid.

3. .The process of synthesizing 1,4-dica1ieyl-quinic acid, whichcomprises condensing 1 to 4 mols of a cafieic acid derivative of thetype with a 3% barium hydroxide solution for one to forty 7 hours at 0to 30 C. in the absence of air.

yield thionyl-caflfeic acid chloride and condensing the latter withquinic acid by heating the two together, and saponifying thecondensation product with aqueous barium hydroxide.

I UNITED STATES PATENTS References Cited in the file of this patent2,587,641 Moersch Mar. 4, 1952 2,686,788 Moore Aug. 17, 1954 FOREIGNPATENTS 7 204,886 Australia Dec. 4, 1956 OTHER REFERENCES Fischer eta1.: Berichte, vol. 46, pp. 4035-6 (1913).

Josephson: Berichte, vol. 61, pp. 911-17 (1928).

Beilstein: 'Handbuch der Org. Chem., vol. XIX, 1st Supp.,'p. 7577(1934).Beilstein: Handbuch'der Org. Chem., vol. X, 2nd Supp., p. 296 (1949).

Luigi Panizzi and Maria Luisa Scarpati: Gazzetta Chimica Italiana, vol.84, pp. 798-805, August 1954.

Luigi Panizzi, Maria Luisa Scarpati and Rachel Scarpati, Gazetta ChimicaItaliana, vol. 84, pp. 806815, August 1954.

1. THE PROCESS OF SYNTHESIZING 1,4-DICAFFEYL-QUINIC ACID, WHICHCOMPRISES CONDENSING A CAFFEIC ACID DERIVATIVE OF THE TYPE